EP2460513B1 - Verfahren zur Herstellung von Adapalen-Gelen - Google Patents

Verfahren zur Herstellung von Adapalen-Gelen Download PDF

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Publication number
EP2460513B1
EP2460513B1 EP12156072.6A EP12156072A EP2460513B1 EP 2460513 B1 EP2460513 B1 EP 2460513B1 EP 12156072 A EP12156072 A EP 12156072A EP 2460513 B1 EP2460513 B1 EP 2460513B1
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EP
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Prior art keywords
adapalene
medium
propylene glycol
poloxamer
gel
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English (en)
French (fr)
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EP2460513A1 (de
Inventor
Maurice Ebel
Richard Dugat
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Galderma Research and Development SNC
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Galderma Research and Development SNC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the invention is in the domain of manufacturing processes and relates to the manufacture of adapalene aqueous gel at industrial level.
  • Adapalene is a retinoid derived from naphthoic acid. It is 6-[3-(1-adamantyl)- 4-methoxyphenyl]-2-naphthanoic acid and has been described in EP 0 199 636 . A method for synthesizing this component has been described in EP 0 358 574 . Adapalene is marketed in the form of an alcoholic solution, an aqueous gel and a cream, at a weight concentration of 0.1 %. These compositions are intended for the treatment of acne.
  • WO 03/075908 describes the use of adapalene at a weight concentration of 0.3 % in an aqueous gel, for the treatment of dermatological disorders.
  • WO 2006/048747 describes adapalene gel preparations and a method to prepare such a preparation.
  • Classical formulation processes are known to need that mixture is cooled to obtain an adequate mixing of all ingredients which induced additional industrial equipment.
  • the inventors now report a new and advantageous method for producing such adapalene aqueous gels, at industrial level.
  • a subject of the present invention is thus a method for producing an adapalene aqueous gel, which method comprises the steps of:
  • the gelling agent in step i) is added after propylene glycol.
  • the pH is adjusted to about 4.7-5.3.
  • each step is advantageously carried out at room temperature. Therefore, drawbacks of classical formulation processes are overcame with the present invention.
  • the medium A further contains a preservative agent which is dissolved in propylene glycol at room temperature.
  • the preservative agent is preferably methylparaben.
  • the medium A further contains EDTA disodium which is dissolved in water before addition of propylene glycol and the gelling agent.
  • the gelling agent is preferably Carbopol 980.
  • the surfactant is a non-ionic surfactant and preferentially a block copolymer surfactant and more preferred a poloxamer as example poloxamer 182, poloxamer 124 and is preferentially Poloxamer 124 (Polyethylene-Polypropylene Glycol also known as Pluronic® L44).
  • the adapalene quantity range is from 0.01% to 1%, preferably from 0.1% to 0.3% and the weight ratio of adapalene/water in the adapalene medium B is between 6% and 23% and preferably between 6 % and 20%.
  • the said method comprises the steps of:
  • the sodium hydroxide is added after step (iii).
  • the pH is adjusted to about 4.7-5.3.
  • adapalene gel obtainable by the said method and the gel produced following the method as described earlier.
  • an adapalene aqueous gel means a gelified aqueous composition, that is preferably monophasic, and that contains adapalene, preferably as a sole active ingredient that shows a cosmetic or therapeutic effect, and preferably in a dispersed state.
  • Adapalene is present in the gel in a therapeutically efficient quantity. It ranges from 0.001 % to 5% and preferably ranges from 0.01 % to 1 % in weight, typically between 0.1% and 0.3% in weight, with regard to the total weight of the aqueous gel. In a preferred embodiment 0.3% is preferred.
  • step i) The addition of propylene glycol at a very early stage in the process is a particular feature of the invention. By very early stage it should be understood the first step and particularly in step i) of the process. Therefore, in a specific embodiment, the gelling agent in step i) is added after propylene glycol.
  • the current invention is based in a specific embodiment on the solubilisation of the preservative in the propylene glycol at 1 to 10%, preferably about 4-5%.
  • This preservative agent is advantageously present in a quantity sufficient for inhibiting microbial growth in the gel during storage and particularly at 0.01% to 3% with regard to the total weight of the aqueous gel.
  • the preservative agent is selected from the following agents: benzalkonium chloride, bronopol, chlorhexidin, chlorocresol and derived products thereof, ethylic alcohol, phenethylic alcohol, phenoxyethanol, potassium sorbate, benzylic alcohol, diazolidinylurea, parabens, or mixture thereof.
  • This preservative agent is preferably selected from the paraben family.
  • it can be methylparaben.
  • This solubilisation is obtained advantageously at room temperature, with common stirring equipment at low or moderate speed.
  • This represent an advantage for manufacturing process as it avoids to heat the gelling medium A, so at industrial level, this invention advantageously reduce manufacturing duration and energy used.
  • Medium A further comprises a chelating agent.
  • the chelating agent is ethylene diamine tetraacetic acid (EDTA) or one of its salts, such as EDTA disodium, as an additional ingredient.
  • EDTA or its salts is useful to chelate metal cations that may be present as impurities in the composition, which makes it possible to avoid side effects in certain patients.
  • EDTA further inhibits browning of the composition during storage of the gel.
  • the gels prepared according to the method of the invention advantageously contain EDTA, or its salts, preferably EDTA disodium, in an amount of 0.05 to 0.5 %, typically about 0.1 %.
  • EDTA or EDTA disodium
  • water is dissolved in water before addition of propylene glycol and the gelling agent.
  • the gelling agent is adapted to make a gel out of an aqueous medium. It is preferably a hydrodispersible polymer that exhibits a high affinity with water. This polymer preferably contains free carboxylic groups that are all or partly neutralised in a form of carboxylate through the use of a base.
  • Preferred gelling agents are vinyl polymers with hydrodispersible carboxylate groups, such as a polyacrylic acid gel, that is neutralised by a base, e.g. sodium hydroxide. Also preferred are polymers with a molecular weight of about 1 250 000 to 4 000 000. Cross-linked polyacrylic acids with such as polyacrylic acid reticulated with polyalkenyl polyethers are also encompassed.
  • Suitable gelling agent are selecting from the following list: electrolytes non sensible carbomers, sold with the tradename Ultrez 20®, Carbopol 1382 or Carbopol ETD2020® by BF Goodrich company, xanthane gum such as Xantural180® sold by Kelco company, guar gum, chitosans, carraghenanes, cellulose and the derivatives hydroxypropylmethylcellulose particularly the product sold with the tradename Methocel E4 premium by Dow Chemical company or hydroxyethylcellulose, particularly the product sold with the tradename Natrosol HHX 250® by Aqualon company, family of aluminium or magnesium silicates such as Veegum K sold by Vanderbilt company, family of acrylic polymers coupled with hydrophobic chains such PEG-150/decyl/SMDI copolymer sold with the tradename Aculyn 44 (polycondensat comprising at least as element one polyethyleneglycol with 150 or 180 moles of ethylene oxide, decylic acid and
  • Suitable preferred gelling agents are family of polymers and preferably those called carbomer polymers which are a crosslinked polyacrylate polymer such as carbomer 940, i.e. carbopol® 980 (2-Propenoic acid, polymer with 2,2-bis(hydroxymethyl)propane-1,3-diol 2-propenyl ether) by the Goodrich company or family of polyacrylamides and preferably those called Simulgel 600 or Sepigel 305.
  • carbomer polymers which are a crosslinked polyacrylate polymer such as carbomer 940, i.e. carbopol® 980 (2-Propenoic acid, polymer with 2,2-bis(hydroxymethyl)propane-1,3-diol 2-propenyl ether) by the Goodrich company or family of polyacrylamides and preferably those called Simulgel 600 or Sepigel 305.
  • the gels prepared according to the invention preferably contain from about 0.5 % to about 2 % of the gelling agent, preferably about 1 %, e.g. 1.1 %.
  • the weight ratio of the gelling agent/water in medium A may range 1% to 1,5 %.
  • Adapalene medium B that is advantageously prepared in parallel, is typically a medium wherein adapalene is dispersed.
  • the weight ratio of adapalene/water in the adapalene medium B is between 6% and 23% and preferably between 6 % and 20%.
  • Medium B preferably comprises a surfactant.
  • the surfactant may preferably be selected from ethylene oxide and propylene oxide block copolymers, and their mixtures, and, preferably, the gel is devoid of any surfactant other than ethylene oxide and propylene oxide block copolymers.
  • the ethylene oxide and propylene oxide block copolymers which can be used as surfactant in the nanoemulsion of the invention can be selected, in particular, from the block copolymers of formula (I) HO(C 2 H 4 O)x(C 3 H 6 O)y(C 2 H 4 O) 2 H, wherein x, y, and z are integers such that x+z ranges from 2 to 100 and y ranges from 14 to 60, and their mixtures, and more particularly from the above block copolymers having an HLB (Hydrophilic Lipophilic Balance) ranging from 2 to 16.
  • HLB Hydrophilic Lipophilic Balance
  • the suitable surfactants have an HLB from 7 to 9, or many non-ionic of polyoxyethylene and/or polyoxypropylene copolymers type. They must be liquid so as to be incorporated easily in the composition without it being necessary to heat it.
  • the surfactant can be classified, according to their structure, under the generic terms "ionic” (anion, cation, amphoteric) or "non-ionic".
  • the non-ionic surfactants are those which does not dissociate in ions in water and are thus insensitive with the variations of pH.
  • surfactants one uses preferentially, without this list being restrictive, those of the family of Poloxamers and more particularly Poloxamer 124 and/or Poloxamer 182 or such as the propylene glycol, the dipropylene glycol, the propylene glycol dipelargonate, the lauroglycol, the ethoxydiglycol, the sodium docussate.
  • the gels prepared according to the invention may comprise such surfactant in an amount of about 0.1 % to about 0.5%, preferably about 0.2 %.
  • the amount of surfactant in medium B can range, for example, from 0.01% to 0.4% by weigh with respect to the total weight of medium B.
  • the neutralisation of the carboxylic groups in the gelling polymers may be achieved by adding a neutralising agent selected from a base, such as ammoniac, sodium hydroxide, organic amines such as alkylamine, or dialkylamine, trialkyamine, alkanolamine, or dialkanolamine.
  • a neutralising agent selected from a base, such as ammoniac, sodium hydroxide, organic amines such as alkylamine, or dialkylamine, trialkyamine, alkanolamine, or dialkanolamine.
  • Said alkylamine can be selected from methylamine, ethylamine.
  • the pH of the final mixture i.e. after mixing the adapalene medium B in the gelling medium A, is adjusted to about 4.7-5.3.
  • the invention provides a method which comprises the steps of:
  • an adapalene gel obtained obtainable by the method of manufacture described herein.
  • the subject of the invention is that the gel is produced following this method.
  • the gel comprises 0.3% of adapalene.
  • This gel is of particular interest for the treatment of dermatological ailments with an inflammatory or proliferative component, chosen from:
  • the gel is particularly suitable for the treatment of acne such as common acne, and in particular for the treatment of common acne of moderate to moderately severe intensity.
  • Figure 1 is a flow diagram that illustrates the manufacturing process of adapalene gel.
  • EXAMPLE 1 manufacturing process of adapalene gel 0.3 % (2000kg)
  • EXAMPLE 2 manufacturing process of adapalene gel 0.1 % (2000kg)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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Claims (6)

  1. Verfahren zum Herstellen eines wässrigen Adapalen-Gels im industriellen Maßstab, wobei das Verfahren in der Reihenfolge die folgenden Schritte umfasst:
    i) des Zubereitens eines Geliermediums A durch Mischen und Lösen von Dinatrium-EDTA in Wasser vor der Zugabe von Propylenglykol, und durch Zugeben eines Geliermittels nach Propylenglykol, das ausgewählt ist aus Xanthan-Gum, Guar-Gum, Chitosan, Karrageen, Zellulose, Hydroxypropylmethylzellulose, Hydroxyethylzellulose, Aluminiumsilicat, Magnesiumsilicat, Acrylpolymer gekoppelt mit hydrophoben Ketten, modifizierte Stärke, eine Mischung aus Natriumacryloyldimethyllaurat-Copolymer/Isohexadecan/Polysorbat 80 und einer Mischung aus Polyacrylamid/Isoparaffin C13-14/Laureth-7, wobei das besagte Medium A ferner ein Konservierungsmittel enthält, das in Propylenglykol bei Raumtemperatur gelöst ist;
    ii) des Zubereitens eines Adapalen-Mediums B durch Dispergieren von Adapalen in Wasser, in Gegenwart eines Tensids;
    wobei die Schritte i) und ii) parallel ausgeführt werden oder einer der Schritte i) oder ii) nach dem anderen ausgeführt wird;
    iii) des Zugebens des Adapalen-Mediums B zum Geliermedium A;
    iv) des Einstellens des pH-Werts auf 4,7-5,3 durch Zugeben eines Neutralisationsmittels,
    wodurch ein Gel gebildet wird,
    und wobei jeder Schritt bei Raumtemperatur durchgeführt wird.
  2. Verfahren nach Anspruch 1, wobei das Konservierungsmittel Methylparaben ist.
  3. Verfahren nach Anspruch 1 oder 2, wobei das Tensid Poloxamer ist.
  4. Verfahren nach Anspruch 3, wobei Poloxamer Poloxamer 124 ist.
  5. Verfahren nach einem der Ansprüche 1 bis 4, wobei der Adapalenmengenbereich von 0,01% bis 1% ist, bevorzugt von 0,1% bis 0,3%.
  6. Verfahren nach einem der Ansprüche 1 bis 5, wobei das Gewichtsverhältnis von Adapalen/Wasser im Adapalen-Medium B zwischen 6% und 23% ist und bevorzugt zwischen 6% und 20%.
EP12156072.6A 2007-11-27 2008-11-27 Verfahren zur Herstellung von Adapalen-Gelen Active EP2460513B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US99661807P 2007-11-27 2007-11-27
EP07121665A EP2065032A1 (de) 2007-11-27 2007-11-27 Verfahren zur Herstellung von Adapalen-Gelen
EP08855104.9A EP2224906B1 (de) 2007-11-27 2008-11-27 Verfahren zur herstellung von adapalen-gelen
PCT/EP2008/066339 WO2009068610A1 (en) 2007-11-27 2008-11-27 A method for producing adapalene gels

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
EP08855104.9 Division 2008-11-27
EP08855104.9A Division EP2224906B1 (de) 2007-11-27 2008-11-27 Verfahren zur herstellung von adapalen-gelen
EP08855104.9A Division-Into EP2224906B1 (de) 2007-11-27 2008-11-27 Verfahren zur herstellung von adapalen-gelen

Publications (2)

Publication Number Publication Date
EP2460513A1 EP2460513A1 (de) 2012-06-06
EP2460513B1 true EP2460513B1 (de) 2021-07-21

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Application Number Title Priority Date Filing Date
EP07121665A Withdrawn EP2065032A1 (de) 2007-11-27 2007-11-27 Verfahren zur Herstellung von Adapalen-Gelen
EP08855104.9A Active EP2224906B1 (de) 2007-11-27 2008-11-27 Verfahren zur herstellung von adapalen-gelen
EP12156072.6A Active EP2460513B1 (de) 2007-11-27 2008-11-27 Verfahren zur Herstellung von Adapalen-Gelen

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Application Number Title Priority Date Filing Date
EP07121665A Withdrawn EP2065032A1 (de) 2007-11-27 2007-11-27 Verfahren zur Herstellung von Adapalen-Gelen
EP08855104.9A Active EP2224906B1 (de) 2007-11-27 2008-11-27 Verfahren zur herstellung von adapalen-gelen

Country Status (13)

Country Link
US (1) US8404220B2 (de)
EP (3) EP2065032A1 (de)
JP (2) JP5526035B2 (de)
KR (1) KR101563379B1 (de)
CN (2) CN103830163B (de)
AR (1) AR071737A1 (de)
AU (1) AU2008328764B2 (de)
BR (1) BRPI0819026B8 (de)
CA (1) CA2706379A1 (de)
ES (2) ES2464455T3 (de)
MX (1) MX2010005432A (de)
RU (1) RU2476203C2 (de)
WO (1) WO2009068610A1 (de)

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FR2910320B1 (fr) 2006-12-21 2009-02-13 Galderma Res & Dev S N C Snc Emulsion comprenant au moins un retinoide et du peroxyde de benzole
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FR2991177B1 (fr) 2012-06-01 2014-12-19 Galderma Res & Dev Compositions topiques, contenant un retinoide, de type emulsion huile dans eau sans emulsionnant
CN103099775B (zh) * 2012-10-08 2014-12-31 天津金耀集团有限公司 阿达帕林凝胶
AU2013352054A1 (en) 2012-11-28 2015-06-04 United-Ah Ii, Llc Method for synchronizing time of insemination in gilts
TW201625218A (zh) * 2014-04-18 2016-07-16 Ｊｂｓ聯合動物保健有限責任公司 製造含ｇｎｒｈ凝膠之方法
CN105411999A (zh) * 2015-11-23 2016-03-23 安徽新和成皖南药业有限公司 一种阿达帕林凝胶的制备方法
US9987239B1 (en) 2017-03-14 2018-06-05 Rey Ventures, LLC Pharmaceutical retinoid preparation for topical use
CN111759798A (zh) * 2017-12-21 2020-10-13 兆科（广州）眼科药物有限公司 一种凝胶制剂中阿达帕林的分散工艺
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BRPI0819026A2 (pt) 2017-04-04
KR101563379B1 (ko) 2015-10-26
CN101878022B (zh) 2014-02-19
MX2010005432A (es) 2010-06-02
ES2887225T3 (es) 2021-12-22
JP2014101373A (ja) 2014-06-05
CN103830163B (zh) 2016-12-07
ES2464455T3 (es) 2014-06-02
CN101878022A (zh) 2010-11-03
EP2065032A1 (de) 2009-06-03
RU2476203C2 (ru) 2013-02-27
JP5526035B2 (ja) 2014-06-18
EP2224906A1 (de) 2010-09-08
US8404220B2 (en) 2013-03-26
US20100280121A1 (en) 2010-11-04
AU2008328764A1 (en) 2009-06-04
JP2011504912A (ja) 2011-02-17
KR20100098539A (ko) 2010-09-07
CN103830163A (zh) 2014-06-04
EP2460513A1 (de) 2012-06-06
RU2010126103A (ru) 2012-01-10
BRPI0819026B8 (pt) 2021-05-25
BRPI0819026B1 (pt) 2020-05-05
EP2224906B1 (de) 2014-02-19
AU2008328764B2 (en) 2013-11-21
AR071737A1 (es) 2010-07-14
WO2009068610A1 (en) 2009-06-04
CA2706379A1 (en) 2009-06-04

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